Apolipoprotein E (apoE) is important in modulating the catabolism of triglyceride rich lipoproteins. ApoE-2 is an abnormal form of apoE associated with type III hyperlipoproteinemia (HLP), but interestingly most subjects with apoE-2 are normolipidemic. These subjects were therefore evaluated for abnormalities in the kinetics of lipid and apoE metabolism. Following a high fat meal, normolipidemic subjects with apoE-2 had elevated triglycerides and triglycerides peaked later than in normals. In addition they had elevated apoE concentrations due to overproduction. Normolipidemic apoE-2 subjects therefore have defects in post-prandial triglyceride and apoE metabolism. Type III HLP subjects have decreased concentrations of LDL. LDL kinetic studies were performed in type III subjects and the results indicated that LDL from type III patients was catabolized more slowly than normal LDL in both normal and type III subjects while type III subjects catabolized type III and normal LDL faster than normal subjects. Therefore the low LDL concentrations in type III HLP are determined by a complex interplay of 1) decreased metabolism of type III LDL, 2) an up regulation of the LDL catabolic pathway and 3) block in the conversion of VLDL to LDL. ApoA-I is secreted into plasma as proapoA-I. The conversion of proapoA-I to mature apoA-I was evaluated in humans. ProapoA-I was rapidly converted to mature apoA-I afterwhich apoA-I was catabolized at the normal rate. Therefore there is a specific and rapid conversion in plasma of proapoA-I to apoA-I. Tangier's disease with low HDL concentrations results from an abnormal apoA-I. Other investigators have proposed that the defect is an inability to convert proapoA-I to mature apoA-I and that proapoA-I Tangier is catabolized rapidly resulting in the lipoprotein abnormalities of this disease. ProapoA-I Tangier was injected into normal and Tangier subjects and was found to be converted normally to the mature form, but the mature form was catabolized very rapidly. Therefore the abnormality in apoA-I Tangier is in the mature form and there is normal conversion of the pro to mature apoA-I Tangier.